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Medications widely prescribed for unproven treatments

By Anne Pinckard

Amy Feldman

An analysis of 725 million prescriptions revealed that 21 percent were for treatments lacking approval from the U.S. Food and Drug Administration. The majority of those without FDA review had little or no other independent scientific justification.

Randall Stafford

In choosing which drugs to prescribe, doctors often select medications for patients despite a lack of conclusive medical evidence of their effects and safety, according to a new study led by a medical school researcher.

Of a wide sampling of prescriptions dispensed to patients in 2001, 21 percent were intended to treat medical conditions for which the drugs lacked specific approval from the U.S. Food and Drug Administration, though other published research suggested possible benefits. Furthermore, about three of every four of those prescriptions lacking FDA approval were for conditions for which there was little or no evidence of the drugs' effectiveness.

This practice of "off-label prescribing" offers doctors flexibility and innovation in treating patients but also carries unknown risks. The findings, which were published May 8 in the Archives of Internal Medicine, were calculated using a sizeable database of the actual number of off-label prescriptions among the 100 most-used drugs and 60 other randomly-selected, commonly used medications.

The results show scientific evidence plays only a partial role in a physician's treatment decisions, said Randall Stafford, MD, PhD, associate professor of medicine at the Stanford Prevention Research Center and senior author of the study. Indeed, many doctors might be unaware if a drug has been FDA-approved for a specific use or how much research supports its use, he added.

"Many doctors prescribed a drug when there is little or no evidence supporting its efficacy and safety," Stafford said. "The study can't tell us why doctors prescribe drugs off label. Some uses are more reasonable than others, but, by definition, off-label uses receive less scrutiny than FDA-approved indications."

It is unclear how off-label uses become established within the medical community in cases where limited or no scientific evidence backs up their use. Informal communication between physicians, promising scientific studies and pharmaceutical industry marketing could play roles, Stafford said. (While nothing prevents a doctor from prescribing a drug off-label, pharmaceutical companies are prohibited from directly promoting such uses.)

Of course, just because a drug is unapproved by the FDA doesn't mean it's ineffective. The FDA approves drugs for treating specific indications only, and there are many reasons why a drug might not have been approved for treating a particular condition, Stafford said. Undertaking the trials needed for approval, for instance, can be time-consuming and expensive. If a drug's patent has expired, a company is unlikely to pursue approval for another indication.

What's more, many drugs belong to classes of pharmaceuticals that work in similar ways, though each might have different side effects. It would be logical to assume that a drug in a particular class would have the same effect as others in that class. Other off-label use may represent an extension of labeled uses or evolving new uses that have not been evaluated stringently. Greater caution is advised in such circumstances.

"These off-label uses have not been scrutinized the way FDA-approved uses have been," Stafford explained. "While this situation is more risky, some patients might have conditions where taking such risks might be warranted."

For patients with severe medical conditions, the potential benefits of treatment might outweigh the increased risk associated with off-label use. A physician might choose to prescribe a drug off-label to adjust for a patient's sensitivities, to avoid interactions with other drugs or to try a different approach if FDA-approved drugs haven't worked.

With colleague and first author David C. Radley, MPH, of Dartmouth Medical School's Center for Evaluative Clinical Sciences, and collaborator Stan N. Finkelstein, MD, of the Massachusetts Institute of Technology, Stafford compiled data taken from the 2001 National Disease Therapeutic Index, a continuing survey of U.S. physicians conducted by IMS Health, a pharmaceutical and health-care marketing company based in Plymouth Meeting, Pa. The survey compiles data from 3,500 physicians who report information about patient care during two randomly selected, consecutive workdays every quarter. The data represents 403,957 encounters between doctors and patients.

According to the IMS Health data, the 160 drugs selected for the study accounted for an estimated 725 million annual prescriptions. About 575 million, or 79 percent of the total, were prescribed for a condition approved by the FDA. Off-label prescriptions accounted for 150 million, or 21 percent of the total number. Of those, 27 percent were for indications supported by scientific evidence, while the remaining 73 percent, or 109 million prescriptions, had little or no evidence.

The team considered a drug's use scientifically supported if the indication appeared with an evidence rating of "good"or "excellent" in DRUGDEX, a nationally recognized pharmaceutical compendium. Rigorous observations in clinical settings and controlled trials must determine the drug's efficacy before such a rating is assigned.

The drug gabapentin was prescribed off-label most frequently—about 83 percent of its total prescriptions. In 66 percent of these instances, the drug had little or no scientific evidence for its efficacy in treating the indication. As of 2001, the FDA had approved gabapentin as an anticonvulsant and as a pain reliever for patients with shingles. Scientific evidence supported its use for social anxiety, migraine prevention and certain diabetic conditions. But doctors commonly prescribed it to treat bipolar disorder and chronic pain, uses not evidenced by adequate scientific scrutiny.

Stafford said better communication and education for both the physician and patient about off-label use is crucial to good health care. "Patients as well as physicians need to ask what's the level of evidence for using a specific drug for a specific condition," Stafford said. "Empowering patients to ask about the level of supporting evidence and to have the physicians adequately respond to these questions will improve patient care."

This study was funded by a grant from the Agency for Healthcare Research and Quality.

Anne Pinckard is a science-writing intern in the medical school's Office of Communication & Public Affairs.